6-Methyl-1,3,8-trichlorodibenzofuran (
MCDF) binds with moderate affinity to the aryl
hydrocarbon (
Ah) receptor protein (4.9 x 10(-8) M) but is a weak
Ah receptor agonist. Cotreatment of male Long Evans rats with
MCDF (50 mumol/kg) and a dose of
2,3,7,8-tetrachlorodibenzo-p-dioxin (
TCDD) that causes a near-maximal induction of hepatic microsomal aryl
hydrocarbon hydroxylase and
ethoxyresorufin O-deethylase activities resulted in a significant inhibition of these activities for up to 96 hr. Comparable results were obtained with
MCDF (10(-7) M) and
TCDD (10(-8) M) in rat
hepatoma H-4-II E cells in culture over 36 hr.
TCDD treatment of rats resulted in an initial decrease of hepatic cytosolic
Ah receptor within 6 hr and this was followed by a subsequent 138% increase in cytosolic receptor levels 72 hr
after treatment. Although
MCDF (50 mumol/kg) did not significantly alter rat hepatic cytosolic
Ah receptor levels in animals cotreated with
TCDD plus
MCDF, the latter compound significantly inhibited
TCDD-mediated replenishment of the cytosolic
Ah receptor. In contrast, treatment of rat
hepatoma H-4-II E cells with
TCDD (10(-8) M) resulted in the rapid (within 1 hr) depletion of cytosolic
Ah receptor, which remained undetectable for up to 36 hr; cotreatment of the cells with
MCDF (10(-7) M) and
TCDD (10(-8) M) resulted in cytosolic
Ah receptor levels that were similar to those observed
after treatment with
TCDD alone. The effects of
MCDF on the uptake and persistence of nuclear [3H]
TCDD-
Ah receptor complex levels were also determined in rat liver and rat
hepatoma H-4-II E cells in culture.
MCDF did not significantly decrease levels of occupied nuclear
Ah receptor complexes in the rat or rat
hepatoma cells. Moreover, using the
sucrose density gradient assay procedure, the sedimentation coefficients of the cytosolic and nuclear
TCDD-
Ah receptor complexes in the presence or absence of
MCDF were comparable. The results of these and other related studies with 6-substituted-1,3,8-trichlorodibenzofurans suggest that
MCDF may act as a partial
TCDD antagonist by competing with
TCDD for nuclear binding sites.